The major objectives of this proposal are to continue studies on the prevention of rejection of islet xenografts transplanted across closely- related and widely-divergent species barriers; adapt the automated method for mass isolation of human islets to the pig pancreas; determine the possible role of intraislet macrophages in the initiation of autoimmune diabetes; use the SCID mouse for studies on autoimmune diabetes. Indefinite survival of closely-related xenografts (rat to mouse) has been achieved by our laboratory by altering or destroying intraislet macrophages plus temporary immunosuppression and recently by in vitro treatment of rat islets with transforming growth factor beta (TGF-beta) and temporary treatment of the recipients with a monoclonal antibody t interferon-gamma. Marked prolongation of survival of widely-divergent islet xenografts (hamster, human, rabbit to mouse) has been achieved with temporary anti L3T4 treatment of recipients. Studies are now in progress to prevent rejection of widely-divergent xenografts (human, hamster, pig to mouse) by developing procedures for more effective elimination of intraislet passenger leucocytes, use TGF-beta for in vitro treatment of donor islets, treatment of recipients with anti-interferon-gamma or chimeric IL-2 toxin or repeated treatment with alpha-L3T4 and combinations of these approaches. These studies should provide basic information on the immunology of xenografts, and if successful, raise the possibility of using pig islets for human transplantation. Recent studies have provided in direct evidence that intraislet macrophages may play a primary role in the initiation of autoimmune diabetes in animal models. Studies are in progress using islet transplants in the low-dose streptozotocin model to assess the role of intraislet macrophages in this autoimmune model. Studies on human autoimmune diabetes have been initiated using SCID mice for establishment of human islet xenografts and attempting order to determine their effect on the human islet xenografts. If this is successful, then it should be possible to isolate specific cell lines cytotoxic for beta cells and study the role of intraislet macrophages in beta cell destruction.